Macrophages respond to various stimuli to produce angiogenic factors but few mechanistic details are known. We examined the effects of hypoxia, lactate and nicotinamide on the expression of vascular endothelial growth factor by cultured macrophages. These agents were chosen because they down-regulate polyadenosine diphosphoribose levels. Following exposure, conditioned media were analyzed for vascular endothelial growth factor protein. Nicotinamide adenine dinucleotide, polyadenosine diphosphoribose, and vascular endothelial growth factor mRNA were measured in the cellular fraction. Angiogenic capacity of the conditioned media was tested in rabbit corneas and Matrigel implants. All three agents, hypoxia, lactate and nicotinamide, elicited significantly increased levels of vascular endothelial growth factor mRNA and vascular endothelial growth factor in the conditioned media, and these levels were paralleled by their angiogenic activity. Polyadenosine diphosphoribose in the cellular fraction was correspondingly depressed. Anti-vascular endothelial growth factor antibody inhibited most of the angiogenic response whereas anti-basic fibroblast growth factor antibody had little effect. We propose that redox changes associated with the alteration of cellular nicotinamide adenine dinucleotide and polyadenosine diphosphoribose are involved in lactate-mediated VEGF expression.
Giant axonal neuropathies are a group of acquired and inherited human diseases morphologically characterized by accumulation of neurofilaments (NF) in enlargements of preterminal regions of central and peripheral axons. Slow axonal transport was studied in the optic systems of rats treated with 2,5-hexanedione, a toxic compound that produces an experimental model of giant axonal neuropathy. The transport rate of NF and of two other polypeptides of Mr 64,000 and 62,000 were selectively increased. Other components of the slow axonal transport were not affected. Acceleration of labeled NF was also observed when 2,5-hexanedione was given after [35S~methionine administration. Morphometric analysis revealed that the number of NF and the axon size were decreased in regions of optic axons proximal to the enlargements. It is suggested that acceleration of NF transport leads to a longitudinal redistribution of NF: NF decrease proximally and increase distally, forming NF-containing enlargements. Evidence was obtained that polypeptides of Mr 64,000 and 62,000 are cytoskeletal components related to intermediate filaments, normally migrating with the component a of the slow axonal transport. The 2,5-hexanedione axon may provide insight into the pathogenesis of inherited and acquired giant axonal neuropathies and offers a model to investigate the relationship between number of NF and axonal size in central axons.Axonal transport involves the migration of highly ordered complexes of proteins at five distinct rates (1). In mammalian optic axons two groups of proteins, slow component a (SCa) and slow component b (SCb), have transport rates of 0.3 mm/day and 2-3 mm/day, respectively (2). SCa comprises neurofilaments (NF), tubulin, and microtubule-associated proteins, whereas SCb carries over 200 polypeptides, including actin, calmodulin, neuronal-specific enolase, and creatine kinase (3).The use of experimental models has added new insight to the role that disturbances of the axonal transport play in the pathophysiology of human diseases of the central and peripheral nervous systems.Giant axonal neuropathies are a group of diseases comprising toxic as well as inherited conditions (4, 5). The pathological hallmark of these diseases is the presence of masses of NF producing focal enlargements in the preterminal regions of axons. In advanced stages of the neuropathy, the enlargements extend proximally and the distal part of the involved axons eventually undergoes degeneration in several central and peripheral axonal pathways. However, in experimental models no degeneration has been observed in the primary optic pathway despite the presence of numerous enlarged axons (6-8).Methyl n-butyl ketone, n-hexane, and their metabolite 2,5-hexanedione (2,5-HxD) (9, 10) are toxic agents that cause distal giant axonopathies. Methyl n-butyl ketone and n-hexane are widely used as solvents and have caused outbreaks of polyneuropathies among industrial workers (11, 12) and in individuals intentionally inhaling glue vapors (13). The distal gi...
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